Mechanisms regulating the timing of developmental events in the early mouse embryo

生物学中一个悬而未决的基本问题是，是什么保证了特定物种的个体在出生时都大致相同。这种高度可重复的胚胎发育速度也具有临床相关性，因为它对胎儿的健康至关重要：发育迟缓是胎儿和新生儿发病率和死亡率的重要原因；过度生长是导致先天性畸形的重要因素。尽管了解胚胎生长是如何调控的很重要，但我们对这一过程仍然知之甚少。在这项建议中，我们旨在解决这个问题。我们将使用小鼠胚胎作为我们的模型系统进行研究，因为这些胚胎可以进行在人类身上不符合伦理的操作。我们将重点分析胚胎刚植入子宫后的这段时间，因为在这段时间里，研究表明，尺寸过小的胚胎表现出追赶式生长，而尺寸过大的胚胎则会缩小，直到它们与正常胚胎一样大。通过分析尺寸过小和过大的胚胎如何发育成正常胚胎的大小，我们预计我们将了解确保所有胚胎以相似速度生长的过程。具体来说，我们将做三件事：1)我们将通过研究是否通过调节细胞分裂的速度和/或细胞死亡的速度来确定过小和过大的胚胎是如何调节它们的生长速度的。2)我们将确定细胞间交换哪些信号来促进小尺寸胚胎的生长和限制大尺寸胚胎的生长。为此，我们将利用我们的初步观察结果，表明通过整合营养或生长因子来调节生长的途径是重要的。为了测试这一途径的重要性，我们将操纵胚胎细胞对这些输入的反应，以确定哪些驱动了小尺寸胚胎的追赶生长和大尺寸胚胎的生长放缓。我们还将研究这些输入在大小不合适的胚胎中是如何表现不同的。在这段时间里，超大和过小的胚胎调整大小，它们开始形成各种不同类型的细胞，这些细胞将形成不同的器官。因此，我们将研究确保胚胎大小合适的机制如何影响胚胎中不同细胞类型的形成。鉴于胚胎大小对正常妊娠的重要性，我们期望上述研究将帮助我们找到方法来识别和治疗妊娠早期生长速度异常的胚胎。

An unanswered fundamental question in biology is what ensures that individuals of a particular species are all roughly the same size at birth. This highly reproducible rate of embryonic development is also clinically relevant as it is essential for the health of the foetus: retarded growth is an important cause of foetal and neonatal morbidity and mortality; over-growth is an important contributor to congenital malformations. In spite of the importance of understanding how embryo growth is regulated, we still know very little about this process. In this proposal we aim to tackle this problem. We will perform our studies using the mouse embryo as our model system as these embryos are amenable to manipulations that would not be ethical in humans. We will focus on analysing the period just after the embryo has implanted into the uterus, as during this period it has been shown that undersized embryos display catch-up growth and oversized embryos reduce in size until they are the same size as normal embryos. By analysing how undersized and oversized embryos scale to the size of normal ones we anticipate that we will gain understanding on the processes that ensure that all embryo grow at a similar rate. Specifically, we will do three things:1) We will establish how undersized and oversized embryos adjust their growth rate by studying if it is by modulating the rate at which their cells divide and/or the rate at which their cells die.2) We will determine what signals are exchanged between cells to promote the growth of undersized embryos and restrict the growth of oversized embryos. For this we will exploit our preliminary observations that indicate that a pathway that regulates growth by integrating nutrient or growth factors is important. To test the importance of this pathway we will manipulate how the cells of the embryo respond to these inputs to establish which of them drives the catch-up growth of undersized embryos and the slowing down in growth of oversized ones. We will also study how these inputs they act differently in embryos that are not the right size.3) During the period that oversized and undersized embryos adjust their size they start to form all the different types of cells that will form the different organs. For this reason we will study how the mechanisms that ensure the embryos are the proper size affect the formation of the different cell types of the embryo.Given the importance of embryo size for a normal pregnancy, we expect that the above described studies will help us develop methods to identify and treat embryos with abnormal growth rates early on in pregnancy.